ABSTRACT / PROJECT SUMMARY Age-related decline in muscle mass and strength is an important public health issue. Future interventions will depend on identifying the physiologic pathways involved in these muscle changes and consequent physical function. We propose to investigate novel risk factors and identify associated pathways that affect age-related declines in muscle mass, quality, strength and gait speed. Our long term goal is to identify novel risk factors and associated pathways that affect age-related declines in muscle and physical function. The objective is to determine the roles of antioxidant intake, vascular function and mitochondrial function in loss of muscle mass, quality, strength and gait speed in adult men and women, providing new public health insights. We hypothesize that low antioxidant intake, impaired vascular function and lower mitochondrial DNA copy number (mtDNA-CN) will each contribute towards decreased muscle mass, quality, strength and gait speed, even accounting for established risk factors. We will address this work via 4 aims using up to 1,912 participants from a well- characterized cohort, the Framingham Offspring Study. Aim 1 will examine the association of antioxidant intakes (Vitamin C, Vitamin E and total carotenoids) with measures of muscle mass, quality, strength [defined as appendicular lean muscle mass/height2, grip strength-to-arm lean mass ratio (arm muscle quality), change in appendicular lean muscle mass/height2, change in grip strength over time] and change in gait speed. Aim 2 will examine the association of vascular function (assessed by brachial artery resting characteristics, hyperemic flow response and aortic stiffness with measures of muscle mass, quality, strength and change in gait speed. Aim 3 will examine the association of mtDNA-CN with measures of muscle mass, quality, strength and change in gait speed. Finally, Aim 4 will examine the combined effect of the novel risk factors evaluated from Aims 1-3 along with established risk factors (protein intake, physical activity and inflammation), on measures of muscle mass, quality, strength and change in gait speed. We plan to validate the findings from these aims by using a validation cohort, the Cardiovascular Health Study. The expected outcome is evidence for low antioxidant intake, impaired vascular and low mtDNA-CN as novel risk factors for age-related decrease in muscle mass, quality, strength and gait speed. The significance of the proposed work is that it will increase our understanding of individual contributions and combined effect of the proposed novel risk factors on age-related declines in muscle and physical function. This study will provide a strong basis for future multi-modality intervention studies aimed at reducing or preventing age-related declines in muscle and their debilitating consequences among older adults. 1